Weatherly's Woes

LIVER DISEASE

Cirrhosis refers to when a healthy liver is replaced by inert fibrosis. It’s as if the liver didn’t exist. Let's compare cirrhosis to a healthy liver.

*In cirrhosis there is a huge increase in Nitric Oxide release. This causes the blood flow of the gut (splanchnic circulation) to vasodilate dramatically (drop in systemic vascular resistance). This explains why edema preferentially affects the abdomen, causing ascites. When the SVR drops, the BP falls, which results in compensatory SNS and RAAS activation, resulting in swelling and hyponatremia (similar to CHF). You treat Ascites with salt restriction and diuretics (Spironolactone and Furosemide), although very large ascites may need to be acutely drained with a needle (paracentesis). Surgeons can create a vascular shunt in the liver to reduce portal hypertension (TIPS procedure).

STIGMATA OF LIVER DISEASE

Gynecomastia

Jaundice

Ascites

Caput medusae

Spider angioma

Dupuytren’s contracture

Jaundice is caused by hyperbilirubinemia.

Gynecomastia and spider angiomas are caused by high estrogen.

Dupytron’s contracture refers to a shortened finger flexor tendon that’s commonly seen in cirrhosis. One of the patient’s fingers, often the ring finger, is partially flexed when you ask them to open their hand up. The mechanism is unknown.

Ascites and caput medusae are caused by portal hypertension.

PORTAL VEIN ANASTOMOSES

This is what happens when the portal vein is blocked. It’s known as portal vein hypertension. This is seen in several different liver diseases, most commonly with cirrhosis.

PORTAL HYPERTENSION

All of these diseases cause portal hypertension

Cardiac Cirrhosis refers to liver swelling caused by CHF. CHF causes fluid to back up. Eventually, it reaches the liver. Fluid accumulates inside of the liver, resulting in hepatomegaly and belly pain. If you did an autopsy and cut this liver in half, the cross-section would look splotchy like the cross-section of a nutmeg (nutmeg liver). Importantly, jugular venous distension is present with CHF.

Budd-Chiari Syndrome refers to a hepatic vein blood clot. It causes portal hypertension, plus a swollen liver. The swollen liver results in abdominal pain, hepatomegaly and a nutmeg liver. There is no jugular vein distension, which can help you differentiate it from cardiac cirrhosis. The causes are pretty weird, like polycythemia vera, pregnancy, oral contraceptives, paroxysmal nocturnal hemoglobinuria and lupus anticoagulant disorder. The hepatic vein can also be externally compressed by a cancer like hepatocellular carcinoma.

Cirrhosis is the most common cause of portal hypertension. It’s discussed in detail elsewhere.

A portal vein thrombosis is an obstructive blood clot in the portal vein. It causes portal hypertension. Unlike the other causes above, there is no liver swelling. That means there is no hepatomegaly. It has the same causes as Budd-Chiari syndrome.

ALCOHOLIC LIVER DISEASE

Alcoholic Liver Disease occurs in three steps.

Fat (steatosis) - ethanol is an energy rich molecule. It’s typically converted to fat in the liver and is deposited in the hepatocytes. This is asymptomatic, although the liver will naturally expand as it fills up with fat. The labs will be pretty unimpressive. The AST and ALT will be in the low hundreds, with the AST being larger. Alcoholic steatosis is reversible if you quit boozing.

Burn (hepatitis) - fatty things are flammable, like cooking oil. The fat in our bodies is also flammable, because it’s pro-inflammatory. Filling up the liver with fat is like making a molotov cocktail. Every few months, alcoholics will suffer an acute flare of liver turmoil (alcoholic hepatitis). They’ll look like they have viral hepatitis (RUQ pain, fever, jaundice), although the AST and ALT won’t be NEARLY as high (both less than 400). The buildup of acetaldehyde also plays a big role, it causes the intermediate filaments inside hepatocytes to collapse into little snake-shaped scribbles (Mallory bodies).

Scar (cirrhosis) - after enough burns, all that remains is a scar. When hepatocytes are killed off, the nearby Ito cells replace them with fibrosis that tends to coalesce into nodules. These fibrous lumps block the flow of blood, which backs up into other parts of the body and causes some of the characteristic symptoms of cirrhosis. The scarring is more compact than the original hepatocytes, so scarred parts of the liver shrinks. However, the overall liver size in cirrhosis can be small, normal or large.

Cirrhosis - Hepatocytes are pink. Scarring is blue. Note the nodular pattern.

The nodular pattern is still evident on gross inspection.

ACUTE LIVER FAILURE

Acute Liver Failure refers to the rapid development of liver necrosis, usually in someone without a history of liver disease. It’s deadly.

Causes include tylenol toxicity, liver hypoperfusion (shock liver), Budd-Chiari syndrome and viral / autoimmune / alcoholic hepatitis. Notably, NASH, hemochromatosis, PBC, PSC and a1ATD cannot cause this. You should get an ultrasound to rule out Budd-Chiari, give them some NAC to treat tylenol and ship them to an ICU right away so they can be treated by a liver specialist.

*Synthetic Impairment refers to the inability of the liver to create things, including albumin and clotting actors.

This is a liver lobule. It’s the fundamental unit of the liver.

Zone 1 is damaged by viral hepatitis

Zone 2 is damaged by yellow fever.

Zone 3 is damaged by ischemia, tylenol, alcohol and toxins.

MISCELLANEOUS LIVER DISEASES

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) refers to the accumulation of fat in the liver (steatosis), commonly seen in people who are obese and have insulin resistance. It’s asymptomatic, but can be spotted on ultrasound and CT scans. NAFLD is reversible with weight loss and good glycemic control. NAFLD sometimes progresses into NASH.

NON-ALCOHOLIC STEATOHEPATITIS (NASH) refers to the episodes of acute hepatitis seen in individuals with NAFLD. Symptoms include fever, RUQ pain and jaundice. With each episode, fibrosis is laid down by Ito cells. Left untreated, it will progress into irreversible cirrhosis.

REYE SYNDROME is the deadly liver necrosis that occurs when kids take aspirin during a viral illness. The mechanism is unknown, but they get severe rapid liver failure, confusion and death. Vignettes often won’t specifically say “aspirin,” but instead mention that mom gave them something over the counter. There is only one approved indication for the use of aspirin in kids, which is Kawasaki disease.

ALPHA 1 ANTITRYPSIN DISEASE is a genetic proteinopathy that causes damage to the lungs and liver. Alpha 1 antitrypsin is a protein that protects connective tissue in the lung. It’s made in the liver. Some people can’t properly synthesize it, and the malformed proteins clump up inside the endoplasmic reticulum of the hepatocytes. The broken a1AT molecules contain a lot of polysaccharides (PAS positive) that can’t be easily broken down. It leads to emphysema and cirrhosis in adults in their 30s. See respiratory section for more information.

Ascites can become infected (SPONTANEOUS BACTERIAL PERITONITIS). The organism is usually from the gut flora (E. coli and Klebsiella). They develop fever, abdominal pain and an extremely tender abdomen. There will be neutrophils inside the thoracentesis aspirate. Give Cefotaxime.

AUTOIMMUNE HEPATITIS is self explanatory. The clinical presentation ranges from asymptomatic to bouts of RUQ pain to cirrhosis. You can diagnose it with anti-smooth muscle antibodies (ASMA), and screen for it with ANA. Treat with steroids.

BILIARY ATRESIA refers to when a neonate is born without a biliary tree. They still make bile, but they can’t get it into the intestines. They cannot poop out their bilirubin (pale stools), so it collects in the liver (hepatomegaly), blood (jaundice) and urine (dark pee). Direct bilirubin will be high. The diagnosis is confirmed with an ultrasound. There is a fascinating surgical remedy called the Kasai procedure where a bile conduit is made using the small intestine, but many need a liver transplant.

CHOLANGIOCARCINOMA refers to a rare cancer of the bile duct. Anything that causes chronic biliary inflammation can cause it. The inflammation can be autoimmune (primary sclerosing cholangitis) or infectious (chinese liver fluke). The presenting symptoms usually relate to cholestasis.

LIVER LABWORK

Liver labs are difficult. Make it easier by grouping things.

AST/ALT indicate active liver damage.

Alk Phos indicates biliary obstruction.

Bilirubin is complicated.

When the liver is weak, albumin is low. When the liver is strong, albumin is high.

When the liver is weak, ammonia is high. When the liver is strong, ammonia is low. It causes confusion and asterixis.

Here are some typical labs.

The AST will be more elevated than the ALT in alcoholic liver disease. Shots, shots, shots, shots, shots, shots, everybody!

GGT is mostly similar to Alk Phos. But it has two cool features. (1) It’s more specific to the liver, meaning less bone overlap. (2) It’s elevated after binge drinking, making it a reliable test for alcoholism.

LIVER MASS

Liver abscesses are caused by either a bacteria (gut flora), a protozoa (Entameba histolytica) or a worm (echinococcus). They typically cause a fever.

Most liver abscesses are bacterial. Bacteria reach the liver either via the blood (sepsis) or via bile (ascending cholangitis).

Protozoans can also cause liver abscesses (developing nations). If you drink dirty water, you may ingest the cyst of Entameba histolytica. First, it travels through your intestines (bloody diarrhea). Second, it climbs up the biliary tree to the liver (liver abscess).

Liver abscesses can also be caused by worms (helminths). Echinococcus, the dog worm, is famous for this. Also called Hydatid cysts. They typically have a smooth calcified border (eggshell calcification) with lots of little internal septations. If the cyst ruptures it will send you into anaphylactic shock.

Hepatic Adenoma refers to a benign liver tumor that is particularly common in young women on birth control. They are mostly asymptomatic, although particularly large ones may rupture, leading to sudden abdominal pain and hypovolemic shock. Discontinuing birth control usually causes them to regress. There is a small risk of malignant transformation.

Hepatic Hemangioma (or Cavernous Hemangioma) refers to a benign vascular tumor in the liver. Do NOT biopsy it, or else it may rupture and cause fatal internal bleeding. Big ones require surgery.

Focal Nodular Hyperplasia refers to another benign liver mass that is common in young women. Its characteristic feature is a central stellate scar.

Hepatocellular Carcinoma is a primary liver cancer. It’s usually caused by cirrhosis, but it can also be caused by the aflatoxin from Aspergillus fungus. Suspect this if a stable cirrhosis patient suddenly develops worsening ascites or abdominal pain. Most cases have an elevated alpha fetoprotein.

Hepatic Angiosarcoma is a rare vascular cancer that occurs in the liver. It’s usually caused by exposure to vinyl chloride (works in a PVC pipe factory) or arsenic.

VIRAL HEPATITIS

Viral Hepatitis refers to one of the five viruses that infect liver cells. They all cause an initial 1 to 2 week illness with jaundice, fever, nausea, malaise, RUQ and hyperbilirubinemia. The tell-tale sign of acute viral hepatitis is super elevated AST and ALT (often over a thousand). Hepatitis B and C both have the potential to cause a permanent chronic liver infection, which is worrisome because that can cause cirrhosis. Note that the hepatitis virus doesn’t directly damage liver cells, killer T cells do.

Hepatitis B is unusual among viruses because it uses the reverse transcriptase enzyme to replicate. Its DNA also has a peculiar shape -- part of the genome is double stranded while the rest is single stranded.

↑ This is high yield ↑

HYPERBILIRUBINEMIA

Jaundice diseases

Unconjugated

Extravascular Hemolysis - high levels of UB overwhelm the conjugating ability of the liver.

Newborn Jaundice - underdeveloped UGT, which may allow UB to slip past the immature BBB into the basal ganglia (kernicterus). Treat with UV light!

Gilbert Syndrome (AR) - UGT is wimpy. They get transient jaundice during stress, but they have no real complications. Gilbert is Good!

Crigler-Najjar Syndrome - absence of UGT. This is not compatible with life -- causes fatal neonatal kernicterus.

Conjugated

Dubin-Johnson Syndrome (AR) - can’t put bile into the bile duct. The liver turns dark, but it’s otherwise not clinically significant

Rotor Syndrome - same as Dubin-Johnson, but the liver is not dark.

Biliary Obstruction - the CB in bile backs up into blood. They have pale stool (no urobilinogen) and dark urine. Think gallstones or cancer.

Mixed

Viral Hepatitis - kills hepatocytes (UB) and ductal cells (CB).

TYLENOL TOXICITY

Acetaminophen affliction

Tylenol is quite safe at low doses. But it’s surprisingly toxic if you take a lot. It’s the deadliest drug in many home medicine cabinets. It causes rapid liver failure, with necrosis in zone 3 of the liver lobules. Your liver clears Tylenol in three ways. 90% of metabolism flows through paths 1 and 2.

1. 1. Glucuronidation → harmless metabolite :)
  2. Sulfation → harmless metabolite :)
  3. CYP450 → toxic metabolite (NAPQI) that kills the liver (Zone 3) with free radicals. Your liver has a fire extinguisher on hand (glutathione). But if you run out of glutathione, you’re fucked. There is a life-saving medication (N-acetylcysteine or NAC) that replenishes your glutathione fire extinguisher.